This invention relates to the use of glycogen phosphorylase inhibitors to reduce tissue damage resulting from non-cardiac ischemia in mammals, including human patients.
Glycogen phosphorylase inhibitors constitute a class of compounds which have use in the treatment of diabetes mellitus.
Commonly assigned PCT applications PCT/IB95/00443 and PCT/IB95/00442 disclose the use of certain glycogen phosphorylase inhibitors for the treatment of damage from perioperative myocardial ischemia.
Glycogenolysis in tissues is catalyzed by the enzyme glycogen phosphorylase (GP). In humans, three different isoforms of the enzyme glycogen phosphorylase have been identified to date: these are the human liver isoform (herein referred to as HLGP), the human muscle isoform (herein referred to as HMGP), and the human brain isoform (herein referred to as HBGP). These three isoforms of human glycogen phosphorylase represent the products of three distinct human genes and are closely related as evidenced by sharing 80-83% amino acid identity (C. B. Newgard, D. R. Littman, C. van Gendered, M. Smith, and R. J. Fletterick, J. Biol. Chem. 263:3850-3857, 1988). Note herein that the term glycogen phosphorylase or the abbreviation GP will be utilized to refer to any or all of the three known isoforms of the human glycogen phosphorylase enzyme, any additional human glycogen phosphorylase isoenzymes identified in the future, and to all isoforms of mammalian glycogen phosphorylase enzymes in general. GP enzymes cleave the glycogen macromolecule to release glucose-1-phosphate and a new shortened glycogen macromolecule. Two types of glycogen phosphorylase inhibitors have been reported to date: glucose and glucose analogs for example, Martin, J. L. et al. Biochemistry 1991, 30, 10101! and caffeine and other purine analogs for example, Kasvinsky, P. J. et al. J. Biol. Chem. 1978, 253, 3343-3351 and 9102-9106!. These compounds, and glycogen phosphorylase inhibitors in general, have been postulated to be of potential use for the treatment of NIDDM by decreasing hepatic glucose production and lowering glycemia. Blundell, T. B. et al. Diabetologia 1992, 35, Suppl. 2,569-576 and Martin et al. Biochemistry 1991, 30, 10101!.